MST1 Facilitates Coronary Artery Disease Progression by Linking Vascular Inflammation and Thrombotic Pathways

Background: Coronary artery disease (CAD) remains one of the leading global causes of mortality, with significant evidence suggesting that genetic predispositions and chronic inflammation contribute to its pathogenesis, especially in patients without traditional risk factors. This study investigates the genetic factors and single nucleotide polymorphisms (SNPs) that influence CAD through RNA and protein analyses of CAD-relevant tissues. By examining cross-tissue interactions and associations with clinical outcomes, we aim to uncover mechanisms contributing to CAD beyond established risk profiles.

Methods: In a cohort of 278 CAD patients from the Personalized Risk Prediction in Coronary Artery Disease (PRECAD) study, we analyzed clinical data, genotyping, and RNA/protein profiles from blood, plasma, mammary artery, and epicardial fat collected during coronary artery bypass grafting. We identified SNPs associated with CAD using expression and protein quantitative trait loci (eQTL/pQTL) analyses, colocalization, and Mendelian Randomization (MR), with further cross-tissue RNA and protein correlation analyses and gene ontology profiling to identify functionally relevant pathways.
Results: We identified MST1 as a protein with a CAD-associated SNP signature, with cross-tissue analyses showing that elevated MST1 blood levels were inversely correlated with arterial levels. MST1 blood levels correlated with prior coronary stenting and platelet medication, and arterial proteins associated with MST1 implicated inflammatory, complement and platelet pathways. MEGENA network analysis supported the involvement of MST1 in complement and fibrin formation pathways relevant to CAD.

Conclusion: MST1, synthesized primarily in the liver, may promote CAD by modulation of inflammation, complement and platelet function in blood and arterial wall. This finding suggests MST1’s involvement in pro-atherosclerotic mechanisms that merit further study to clarify its role in CAD pathology (Funded by DigiMed Bayern; PRECAD clinical trial registration number, DRKS00020960).